Chemoenzymatic Synthesis of Modified 2′-Deoxy-2′-fluoro-β-d-arabinofuranosyl Benzimidazoles and Evaluation of Their Activity Against Herpes Simplex Virus Type 1

Abstract

1-(2′-Deoxy-2′-fluoro-β-d-arabinofuranosyl)benzimidazoles containing 4,6-difluoro-, 4,5,6-trifluoro-, 5-fluoro-6-methoxy-, and 5-methoxy-4,6-difluorobenzimidazole fragments were synthesized by using purine nucleoside phosphorylase-catalyzed chemoenzymatic approach. As expected, enzymatic synthesis of nucleosides proceeds in lower yields of target compounds in comparison with the synthesis of ribo- and 2′-deoxyribobenzimidazoles (40–55% vs 60–90%). The compounds obtained were tested against the herpes simplex virus type 1, by using the Vero E6 cells. 5-Methoxy-4,6-difluoro-1-β-d-(2′-deoxy-2′-fluoroarabinofuranosyl)benzimidazole did not show any antiviral activity, when used in nontoxic concentration. All other nucleosides proved to exhibit a selective antiherpes activity. In contrast, it was shown that benzimidazole-β-d-arabinofuranosides of both di- and trisubstituted derivatives, having substituents in positions 4–6 of the benzene ring, as well as unsubstituted compounds, cannot be synthesized by enzymatic transglycosylation. 1-(β-d-Arabinofuranosyl)benzimidazole was obtained through glycosylation of N-trimethylsilylbenzimidazole with 1-chloro-2,3,5-O-methoxymethyl-d-arabinose. The behavior of this compound, as inhibitor of purine nucleoside phosphorylase (PNP) E. сoli, was investigated. 1-(β-d-Arabinofuranosyl)benzimidazole was found to belong to a mixed type of inhibitors of PNP. This fact explains why all attempts to perform enzymatic arabinosylation of 4,6-di-, 5,6-di-, and 4,5,6-trisubstituted benzimidazoles failed.

Key words

drug discovery - herpes simplex virus - fluorine - nucleosides

• References

• 1 De Clercq E. Adv. Virus Res. 2009; 73: 1
• 2 Marty FM, Ljungman P, Papanicolaou GA, Winston DJ, Chemaly RF, Strasfeld L, Young J.-AH. Lancet Infect. Dis. 2011; 11: 284
• 3 Williams SL, Hartline CB, Kushner NL, Harden EA, Bidanset DJ, Drach JC, Townsend LB, Underwood MR, Biron KK, Kern ER. Antimicrob. Agents Chemother. 2003; 47: 2186
• 4 Prichard MN, Frederick SL, Daily S, Borysko KZ, Townsend LB, Drach JC, Kern ER. Antimicrob. Agents Chemother. 2011; 55: 2442
• 5 Alain S, Revest M, Veyer D. Transplant. Proc. 2013; 45: 1603
• 6 Budow S, Kozlowska M, Gorska A, Kazimierczuk Z, Eickmeier H, La Colla P, Gosselin G, Seela F. ARKIVOC 2009; (iii): 225
• 7 Tamm I, Sehgal PB. Adv. Virus Res. 1978; 22: 187
• 8 Townsend LB, Devivar RV, Turk ST, Nassiri MR, Drach JC. Med. Chem. 1995; 38: 4098
• 9 Zou R, Drach JC, Townsend LB. J. Med. Chem. 1997; 40: 802
• 10 Konstantinova ID, Selezneva OM, Fateev IV. Synthesis 2013; 45: 272
• 11 Ojima I. Fluorine in Medicinal Chemistry and Chemical Biology. Wiley; New York: 2009
• 12 Vajpayee M, Malhotra N. Indian J. Pharmacol. 2000; 32: 330
• 13 Shen W, Kim J.-S, Mitchell S. Nucleosides, Nucleotides Nucleic Acids 2009; 28: 43
• 14 Kharitonova MI, Fateev IV, Kaushin AL, Konstantinova ID, Kotovskaya SK, Leont’eva VL, Galegov GA, Charushin VN, Miroshnikov AI. Synthesis 2016; 48: 394
• 15 Averett DR, Koszalka GW, Fyfe JA, Roberts GB, Purifoy DJ, Krenitsky TA. Antimicrob. Agents Chemother 1991; 35: 851
• 16 Konstantinova ID, Antonov KV, Fateev IV, Miroshnikov AI, Stepchenko VA, Baranovsky AV, Mikhailopulo IA. Synthesis 2011; 1555
• 17 Pascual GM, Deroncele TV, Montilla AR. Patent EP 2883959 A1, 2015
• 18 Ekiel I, Darzynkiewicz E, Shugar D. Carbohydr. Res. 1981; 92: 21
• 19 Townsend LB, Drach JC. Patent WO1999051619 A1, 1999
• 20 Townsend LB, Drach JC. Patent US 5360795 A, 1994
• 21 Kondo K, Inoue I. J. Org. Chem. 1977; 42: 2809
• 22 Furukawa Y, Honjo M. Chem. Pharm. Bull. 1968; 16: 2286
• 23 Damaraju VL, Damaraju S, Young JD, Baldwin SA, Mackey J, Sawyer MB, Cass CE. Oncogene 2003; 22: 7524
• 24 Pankiewicz KW. Carbohydr. Res. 2000; 327: 87
• 25 Griengl H, Wanek E, Schwarz W, Streicher W, Rosenwirth B, De Clercq E. J Med Chem. 1987; 30: 1199
• 26 Fateev IV, Antonov KV, Konstantinova ID, Muravyova TI, Seela F, Esipov RS, Miroshnikov AI, Mikhailopulo IA. Beilstein J. Org. Chem. 2014; 10: 1657
• 27 Bzowska A, Kulikowska E, Shugar D. Pharmacol. Ther. 2000; 88: 349
• 28 Esipov RS, Gurevich AI, Chuvikovsky DV, Chupova LA, Muravyova TI, Miroshnikov AI. Protein Expression Purif. 2002; 24: 56
• 29 Holý A, De Clercq E, Votruba I In Nucleotide Analogues as Antiviral Agents, Proceedings of Symposium on Nucleoside Analogues as Antiviral Agents, 196th National Meeting of the ACS, Los Angeles, CA (USA), 25–30 September 1988. Martin JC. American Chemical Society; Washington DC: 1989: 51-71
• 30 Andronova VL, Galegov GA, Yasko MV, Kukhanova MK, Skoblov YuS. Problems of virology 2010; 55: 31
• 31 Gus’kova AA, Skoblov MYu, Korovina AN, Yasko MV, Karpenko IL, Kukhanova MK, Andronova VL, Galegov GA, Skoblov YuS. Chem. Biol. Drug Des. 2009; 74: 382